Antiparasitic and Immunomodulatory Activity of AMPs and CPPs

Version	Summary	Created by	Modification	Content Size	Created at	Operation
1		Javier Carrión	--	4536	2023-07-21 02:21:30	\|
2	format	Jason Zhu	Meta information modification	4536	2023-07-21 05:32:37	\|

This entry is adapted from the peer-reviewed paper 10.3390/pathogens12070939

In 2020, the WHO established the road map for neglected tropical diseases 2021–2030, which aims to control and eradicate 20 diseases, including leishmaniosis and Chagas disease. In addition, since 2015, the WHO has been developing a Global Action Plan on Antimicrobial Resistance. In this context, the achievement of innovative strategies as an alternative to replace conventional therapies is a first-order socio-sanitary priority, especially regarding endemic zoonoses in poor regions, such as those caused by Trypanosoma cruzi and Leishmania spp. infections.

antimicrobial peptides cell-penetrating peptides intracellular pathogen

1. Introduction

The antiparasitic activity of AMPs and CPPs, is carried out through different mechanisms, such as the rupture of the plasmatic membrane, the alteration of calcium homeostasis (excessive accumulation of intracellular Ca²⁺ interferes with metabolism, the disorganization of kinetoplast DNA. and the promotion of autophagy and cell death) ^[1]. CPPs cross the membrane and tend to accumulate directly within the cytoplasm to carry out their antiparasitic activity by interfering with enzymatic activity and nucleic acid synthesis. These peptides may be involved in antiparasitic activity as well as immunomodulatory functions, leading to proper regulation of the inflammatory response to reduce damage to different target organs and control infection ^[2]^[3].

In Table 1, in vitro studies on natural and synthetic AMPs and CPPs against T. cruzi and different Leishmania species are summarized. Many of them were obtained by synthetic routes, although they generally respond to primary structures in the same manner as naturally ocurring peptides. The sources of AMPs and CPPs with antimicrobial activity, can be divided into mammals (human host defense peptides account for a large proportion), plants, amphibians, microorganisms, and insects. However, it is notable that mainly organisms used as primary sources are not common hosts of Leishmania or T. cruzi parasites.

Once internalized, the peptides and/or the cargo they carry can exert their antiparasitic activity. Two main mechanisms of action have been proposed: transient destabilization of membranes and intracellular targets ^[3]. In the case of cationic peptides, it has been suggested that electrostatic interactions based on differences in the compositions of the envelopes of host cells and parasites constitute the determining factor allowing preferential binding to the latter, using the host cell membrane as a means of passage. Binding to the parasite membrane induces its destabilization, which can lead to lysis and a loss of membrane potential. By contrast, when the peptides are anionic, hydrophobic, and amphipathic, the mechanism is elusive. In other cases, the target may be intracellular, such as an enzyme, nucleic acid, or organelle (e.g., mitochondria) ^[4]^[5]. As most AMPs are cationic, one of the mechanisms of action of such compounds is the selective binding to the membrane of the parasites, causing membrane disruption and pore formation ^[6]. Those pores might be formed by the dimerization of the peptides within the membrane upon these electrostatic interactions ^[7]. As previously mentioned, the differences in the external membrane charge between Leishmania life stages are responsible for the dissimilarity in susceptibility to compounds between the promastigote and amastigote forms. The intracellular nature of amastigotes creates additional barriers to the leishmanicidal activity of peptides. In an attempt to increase knowledge on this topic, delivery systems, combinations, and chemical conjugation strategies have been tested. Since lipopeptides produced by Bacillus species target the cytoplasmic membrane and form ion-conducting pores in the lipid membrane, these lipopeptides are endowed with cytotoxicity toward human cells, which limits their biomedical application. Their encapsulation in chitosan nanoparticles, which previously exhibited antileishmanial potential through direct intercalation into the parasitophorous vacuole, enhanced antileishmanial activity ^[8]. This improvement could be related to the progressive release of lipopeptides from the chitosan delivery system ^[9]. This system previously showed effectiveness against experimental cutaneous leishmaniosis using AmB as the incorporated drug ^[10]. Among the strategies used to increase the therapeutic index and reduce the toxic effects of currently available chemotherapy against leishmaniosis, nanocarriers stand out, showing potential as a site-specific drug delivery system ^[11].

2. Synthetic and Bioinformatic Tools

An important advantage of AMPs is their broad potential for synthetic modification ^[12]. The molecular characterization of AMPs makes it possible to generate synthetic derivatives by modifying the primary sequence in order to improve some properties related to target specificity, cytotoxicity, potency, stability, or the active site ^[13]. This flexibility could enable the development of AMPs with optimized therapeutic properties for the treatment of both diseases. Among the most promising scaffolds for drug development, AMPs have been explored as potent antimicrobials because of their versatility and almost unlimited sequence space. These molecules can be easily tuned to achieve broad-spectrum activity, specific activity, or cytotoxicity through changes in the amino acid residues that are part of their sequence ^[14]. These changes give rise to variations in the structural and physicochemical properties that are closely related to their antimicrobial activity ^[15]. Cytotoxic activity may be enhanced by changing the amino acids. The synthesis of peptides bearing the sequence responsible for the biological activity is also useful ^[16]. Additionally, among the different kinds of peptide modifications, fatty acid conjugation to potentiate antimicrobial activity has been a topic of interest. However, the results have not always been as expected ^[17]. Either way, AMPs are toxins produced by organisms, such as frogs or snakes, and can require complex and expensive purification processes to be used as therapeutic agents. The synthetic production of AMP can also be expensive and time-consuming, but this problem can often be overcome through solid-phase peptide synthesis ^[18].

In addition, bioinformatics is a useful tool for active peptide selection. The physicochemical properties, structure, and toxicity of peptides can be predicted using bioinformatic tools in order to detect antimicrobial regions and determine the charge, hydrophobicity, isoelectric point (pI), and peptide mass. Cationic peptides bio-inspired by natural toxins have been recognized as an efficient strategy for the treatment of different health problems. Selected peptide sequences were synthesized and tested against cancer cells, bacteria, and two Leishmania species ^[19]. Another choice is the generation of hybrid peptides. CM11, which consists of the N-terminal domain of cecropin A and the hydrophobic C-terminal domain of melittin, demonstrated the ability to kill Leishmania major promastigotes and amastigotes with no significant cytotoxicity to murine macrophages ^[20]. The production of recombinant peptides using cloning strategies has also been tested. The insect defensin rDef1.3 from Triatoma pallidipennis, a vector of T. cruzi, was produced by transformed Escherichia coli and purified using immobilized metal affinity chromatography. Then, its microbicidal activity was analyzed against trypanosomatid species, including two Trypanosoma species as well as L. major and L. mexicana. Recombinant defensin caused atypical morphology and proliferative activity reduction in Leishmania parasites ^[21].

3. AMPs and CPPs for Combatting Different Forms of Leishmaniosis

The attractive biological activities of AMPs are prompting active research in the therapeutic application of these agents to combat many infectious diseases ^[22]. The first reports of the effects of AMPs on Leishmania were published in 1998, with Hyalophora cecropin A ^[23], cecropin A (1–8)–melittin (1–18) (CAMEL) hybrid peptides ^[24], and components of the target microorganisms, such as macromolecules and organelles ^[25]^[26]. To date, several groups of AMPs and CPPs, such as cathelicidins, cecropins, defensins, dermaseptins, eumenitin, histatins, magainins, melittins, and temporins, among others, have been proven to have significant action against diverse Leishmania species ^[22]^[27]. In this sense, relevant reviews in recent decades ^[5]^[28] have highlighted this group as an exciting alternative for designing new pharmaceutical alternatives against leishmaniosis and have demonstrated the growing list of AMP and CPPs with antileishmanial activity ^[28]. Below, a compilation of previously published studies regarding the action of these molecules against Leishmania is discussed.

The problem faced by traditional drugs in crossing the protozoa membrane and accessing intracellular amastigotes is well known. AMPs are characterized by their high intracellular penetrability. Their antiprotozoal activity could be direct, altering membranes or focused on internal targets, including DNA, RNA and protein synthesis, the lysosomal bilayer, key enzymatic activities, and mitochondria ^[29]. In addition to their ability to permeabilize membranes, recent observations have shown that some peptides can also move to the cytoplasm of the microorganism cell and interact with intracellular targets, interfering with the cell wall, the synthesis of nucleic acids or proteins, and enzymatic activity ^[30]. The high penetrability of AMPs will undoubtedly contribute to a faster mode of action than traditional drugs. This aspect is especially important in Chagas disease, as it will prevent the disease from progressing to the chronic phase. In addition, as a result of their multiple mechanisms of action, AMPs could act synergistically with conventional drugs (such as Bz and nifurtimox) and other AMPs, leading to better treatment outcomes ^[31].

The phospholipase A2 (PPA2)-derived peptides are enzymes commonly present in the venom of organisms from all kingdoms; they have a natural origin and can hydrolyze phospholipids from cell membranes. Short peptides derived from PPA2 can cross the membrane, showing effective activity against Leishmania promastigotes and amastigotes ^[32]^[33]. Interestingly, these cationic peptides, rich in lysine, increase their affinity when lysine is substituted with arginine ^[34]. Another cationic peptide, tachyplesin, derived from the horseshoe crab (Tachypleus tridentatus) has potential against Leishmania spp. and T. cruzi ^[35]^[36]^[37]. Tachyplesin is a 17mer peptide with a net positive charge that interacts with the parasite membrane, seriously compromising its integrity. Bovine lactoferrin-derived peptide also has leishmanicidal activity, which resides in its ability to permeabilize the membranes of promastigotes and axenic amastigotes of L. donovani ^[38].

CPPs can be coupled to cargos and translocated into the cell with high efficiency. Cargos include drugs or biological molecules, such as DNA, antibodies, and proteins ^[39]. Since CPPs can be placed in the membrane of the target cell, they can penetrate and accumulate inside the intracellular compartments, reaching higher local concentrations and overcoming one of the limitations of common drugs ^[28]^[40]. This fact is very interesting, considering the limited concentrations that can be attained in the plasma with common soluble drugs, which are even more limited in intracellular compartments. A few examples have been reported in this regard. Tachyplesine peptides were able to transport the plasmid EGFP-N1 inside parasites, becoming fluorescent ^[37]. Another example is chiral cyclobutane, which contains cell-penetrating peptides. These peptides are highly selective for Leishmania donovani parasites compared with HeLa cells ^[41]. While Leishmania promastigotes were not sensitive to free doxorubicin, the toxicity dropped to <1 µM when conjugated with these peptides, revealing their potential as a vehicle. In addition, when conjugated with TAT (transactivator of transcription), doxorubicin also accumulated inside the parasite, although to a lesser extent than with cyclobutane-CPPs ^[41]. TAT is a positively charged peptide derived from the TAT protein of HIV-1. The TAT protein binds and activates RNA polymerase II during infection ^[42]. TAT is a CPP that can pull cargos across membranes in different systems ^[43]. In Leishmania, TAT facilitates the internalization and accumulation of the antiparasitic miltefosine and paromomycin drugs ^[44]^[45]^[46].

As previously described, an appealing characteristic of AMPs is their ability to exert microbicidal activity by more than one mechanism. The strong post-transcriptional control of gene expression in trypanosomatids makes Leishmania a highly sensitive target to foreign RNases. This is the case for the ECP (eosinophil cationic protein, a human antimicrobial protein), which comprises RNase activity. Recently, Abengózar et al. ^[47] observed that ECP-treated L. donovani promastigotes showed a degraded RNA pattern. This was in agreement with the relationship between the recruitment of eosinophils into Leishmania lesions and favorable evolution. Just as paromomycin induces protein synthesis inhibition in L. donovani promastigotes ^[48], it has been hypothesized that xenocoumacin acts similarly on L. tropica promastigotes ^[49]. Recently, the modulatory effect of AMPs on L. major amastigote gene expression was shown as an additional mechanism ^[27]. The induction of autophagic cell death in the protozoan pathogen L. donovani has been described as an AMP mode of action; for instance, indolicidin and two peptides derived from Seminalplasmin (SPK and 27RP) prompt programmed cell death pathways without affecting host cells ^[50].

In addition, nanodelivery strategies can enhance the activity of peptides. Thus, the frog skin-derived peptide dermaseptin, which has been shown to possess antileishmanial activity ^[51]^[52], was encapsulated into sub-micrometer Cry crystal proteins formed naturally by Bacillus thuringiensis, enhancing the target to macrophage lysosomes. The encapsulation of dermaseptin in Cry crystal proteins improved the leishmanicidal activity of dermaseptin in both in vitro and in vivo infection models ^[53].

Currently, researchers are focusing their attention on the immunomodulatory ability of AMPs and CPPs. For instance, synthetic peptides derived from Limulus anti-LPS factors (LALFs) 19-2.5 and 19-4LF reduced the parasite burden in vivo when topically administered to L. major BALB/c-infected mice by modulating the expression of host genes ^[27]. Although each peptide displayed its own pattern of cytokine modulatory activity, these peptides caused an increase in Th1 cytokine mRNA levels (IL-12p35, TNF-α, and iNOS) in both the skin lesion and the spleen. In addition, in skin lesions from Leishmania-infected mice treated with the peptide 19-4LF, a decrease in IL-4 and IL-6 gene levels was detected, in agreement with the reduction in the parasite burden in these samples ^[27]. Phylloseptin-1 (PSN-1), a peptide found in the skin secretion of the frog Phyllomedusa azurea, showed activity against L. amazonensis promastigotes ^[54] and amastigotes ^[55]. To understand the molecular changes associated with the leishmanicidal effect of PSN-1 against amastigotes, the levels of key cytokines (TGF-β, TNF-α, and IL-12) and the production of reactive species (H₂O₂ and NO) were assessed. The increase in TNF-α release caused by PSN-1 might have participated in the destruction of the amastigotes inside macrophages. The peptide was also observed to up- and down-modulate IL-12 p70 production in infected macrophages in a concentration-dependent manner. Probably, the immunomodulatory effect of the peptide favors the host instead of the parasite by decreasing the pathogenesis while the peptide kills the parasite ^[55]. Amphibians are one of the most abundant reservoirs of AMPs in nature, and their peptides have been explored against different species of Leishmania parasite. Dermaseptin, which was isolated from frog skin secretions of Phyllomedusa genera, has shown activity against L. major ^[35]^[56], L. amazonensis ^[57], L. mexicana ^[58], L. panamensis ^[35] and L. infantum ^[59], agents that cause cutaneous or visceral leishmaniosis and are endemic to the New and Old World. Other frog-derived peptides inhibit the growth of parasites, such as bombinins H2 and H4 ^[60] and temporins ^[61]^[62], at micromolar concentrations. Substantial efforts have been invested in cecropin A and melittin alone or in combination as hybrid molecules (CA-M). In this sense, shortened sequences ^[63], lipid N-terminals ^[64], and N-methylated Lys residues ^[65] showing relevant activity against L. donovani ^[24] and L. pifanoi ^[64] have been designed. In particular, attention was drawn to interesting results displayed by plant thionins with IC₅₀ values < 0.5 μM ^[66], making them among the most efficient antimicrobial peptides; they also showed activity against other human pathogens ^[67]^[68]. However, one of the probable limitations of some of the included studies is related to antileishmanial activity with respect to the stage/form of the parasite targeted. In general, a large number of studies limited their results to the axenic amastigote (i.e., macrophage-free) or promastigote forms, which are not relevant in human infection. In Leishmania, the intracellular amastigote form is consistently more resistant, and their growth in hostile intramacrophagic habitats and membrane surface compositions most likely account for the differences observed upon comparison with promastigotes and axenic amastigotes ^[38]. In addition, few studies have demonstrated the use of AMPs and CPPs in animal models of infection by Leishmania parasites. In this sense, the therapeutic potential of CA-M analogs against canine leishmaniosis has been observed on the basis of infection control through a decrease in the parasite burden and a reduction in disease symptoms ^[69]. The lauric acid-conjugated form of brevinin, a defensin isolated from skin secretions, was administered alone and in combination with the CpG motif to treat BABL/c mice previously inoculated in the hind footpad with L. major metacyclic promastigotes. It is known that CpG motif application is helpful for inducing a specific immune response in experimental models. Brevinin was subcutaneously administered, whereas the CpG motif was applied via the intraperitoneal route five times over 10 days. In this case, in the fifth week after the challenge, the groups that received lauric acid conjugated form of brevinin alone or in combination with the CpG showed showed a significant increase in footpad swelling compared with the group of mice treated with the reference drug Ambisome^®, which was able to notably control footpad swelling ^[70]. However, the parasite load decreased in the popliteal lymph nodes adjacent to the infection site after peptide administration more significantly in groups treated with the brevinin–CpG combination. The production of cytokines in the spleens of mice treated with brevinin did not coincide with parasite replication control results since it was not, as expected, favorable for the Th1 response, which is traditionally accepted as necessary for cutaneous leishmaniosis healing to occur ^[70]. Along the same lines, the frog skin-derived peptide dermaseptin, which has leishmanicidal activity, was encapsulated into crystal proteins and tested against a mouse cutaneous model of infection caused by L. amazonensis. This encapsulation strategy enhanced the peptide efficacy in the in vitro and in vivo infection models. Parasites were inoculated in the hind footpad, and the formulated peptide was intralesionally administered every four days (a total of six times). Repeated injections inhibited lesion growth efficiently. Similarly, encapsulated dermaseptin decreased the parasite burden in the footpads, whereas free peptide administration was unable to reduce the number of amastigotes in the lesions ^[53].

Table 1. AMP and CPPs with antiprotozoal activity against intracellular parasites T. cruzi and/or Leishmania spp.

Peptide Molecule	Source	Antiprotozoal Activity	Reference
Andropin	Synthetic	L. panamensis L. major	^[35]
Anti-lipopolysaccharide factor	Penaeus monodon (marine crustacean)	L. braziliensis	^[36]
BatxC	Bothrops atrox (snake)	T. cruzi (Y strain)	^[71]
Bombinins H2 and H4	Bombina variegata (frog)	L. donovani	^[60]
Cathelicidins (SMAP 29, PG-1)	Synthetic	L. major L. amazonensis	^[72]
Cecropin A, D	Drosophila Hyalaphora cecropia	L. aethiopica L. panamensis	^[23]^[27]
Cecropin A-melittin	Hybrid peptide	L. donovani L. pifanoi	^[24]^[64]
Cecropin A, B, and P1	Synthetic	L. panamensis	^[35]
		L. major
		T. cruzi (Tulahuen strain)	^[73]
Chyral cyclobutanes	Synthetic	L. donovani	^[41]
Clavanin A	Styela clava (sea squirt)	L. braziliensis	^[36]
CM11 (cecropin–melittin hybrid)	Synthetic	L. major	^[20]
Cryptdin-1 and -4	Macaca mulatta (rhesus macaque)	L. major L. amazonensis	^[72]
Ctn	Crotalus durissus terrificus (rattlesnake)	T. cruzi (Y strain)	^[74]
Defensin	Phlebotomus duboscqi (sandfly)	L. major L. amazonensis	^[27]^[75]
Defensin α1	Human	T. cruzi (Tulahuen strain)	^[76]^[77]
Defensin (fragments D, P, B, Q, and E)	Mytilus galloprovincialis (mussel)	L. major	^[78]
Dermaseptin	Phyllomedusa sauvagii (frog)	L. mexicana L. panamensis L. major	^[35]^[58]
Dermaseptin 01	Synthetic	L. infantum	^[59]
Dermaseptin 01, 02, 03, 04, 06, and 07	Phyllomedusa hypochondrialis (frog)	L. amazonensis	^[57]
Dermaseptin S1 analogs	Synthetic	L. major	^[56]
Dhvar4 (histatin 5 analog)	Synthetic	L. donovani	^[79]
DS 01	Phyllomedusa oreades (frog)	T. cruzi (Y strain)	^[80]
Enterocin AS-48	Enterococcus faecalis	L. pifanoi	^[81]
Enterocin AS-48 homologs	Synthetic	L. donovani	^[82]
Eumenitin	Eumenes rubronotatus (wasp venom)	L. major	^[27]
Gomesin	Acanthoscurria gomesiana (tarantula)	L. amazonensis	^[83]
Histatin 5 (L- and D-enantiomers)	Synthetic	L. donovani L. pifanoi	^[79]
Hmc364-382	Dpenaeus monodon (shrimp)	T. cruzi (Y strain)	^[84]
Indolicidin	Synthetic	L. donovani	^[50]
Lactoferricin (17–30) Lactoferrampin (265–284) LFchimera	Bovine milk lactoferrin (domain N1)	L. pifanoi L. donovani	^[38]
LTP2 α-1	Hordeum vulgare (barley)	L. donovani	^[66]
M-PONTX-Dq3a[1-15]/[Lys]³-M-PONTX-Dq3a[1-15]	Dinoponera quadriceps (ant) synthetic modification	T. cruzi (Y strain)	^[85]^[86]
Magainin Magainin analogs (MG-H1/H2) and F5W-magainin 2	Xenopus laevis (frog)	L. braziliensis	^[27]^[36]
		L. major
		L. donovani
	Synthetic	L. amazonensis	^[87]
Melittin	Bee venom Apis mellifera	L. donovani L. infantum L. panamensis L. major T. cruzi (CL Brener strain)	^[27]^[35]^[88]
Mylitin A	Mytilus edulis (mussel)	L. braziliensis	^[36]
NK2	Synthetic	T. cruzi (Tehuantepec strain)	^[89]
Ovispirin	Synthetic	L. major L. amazonensis	^[72]
p-Acl and analog p-AclR7	Synthetic	L. amazonensis L. infantum	^[33]
Penaeidian-3	Whiteleg shrimp Litopenaeus vannamei	L. braziliensis	^[36]
Rhesus	Synthetic	L. major L. amazonensis	^[72]
Phylloseptin-1	Synthetic	L. amazonensis	^[54]
Polybia-CP	Polybia paulista (wasp)	T. cruzi (Y strain)	^[90]
PTH-1	Solanum tuberosum (potato)	L. donovani	^[66]
Pr-1, 2, and 3	Synthetic	L. panamensis L. major	^[35]
Pylloseptin 7	Phyllomedusa nordestina (frog)	T. cruzi (Y strain)	^[91]
SALPs	Synthetic	L. major	^[27]
Snakin-1	Solanum tuberosum (potato)	L. donovani	^[66]
Seminalplasmin (SPK and 27RP)	Synthetic	L. donovani	^[50]
StigA25	Tityus stigmurus (scorpion) Synthetic	T. cruzi (Y strain)	^[92]
Tachyplesin	Tachypleus tridentatus (horseshoe crab)	L. panamensis L. major L. braziliensis L. donovani T. cruzi (Y strain)	^[35]^[36]^[37]^[93]
TAT (48–57) peptide TAT (48–60) peptide TAT and polyarginine	TAT (transactivator of transcription) protein from HIV-1	L. donovani L. infantum	^[41]^[44]^[45]
Temporins A and B	Rana temporaria (frog)	L. donovani L. pifanoi	^[27]^[62]
Temporin-1Sa, 1Sb, and 1Sc	Pelophylax saharica (frog)	L. infantum	^[61]
Temporizin-1	Synthetic	T. cruzi (Y strain)	^[94]
Thionin α-1, α-2, and β type I	Triticum aestivum (wheat) Hordeum vulgare (barley)	L. donovani	^[66]
[Arg]¹¹-VmCT1	Vaejovis mexicanus (scorpion)	T. cruzi (Y strain)	^[95]

4. AMPs and CPPs to Combat T. cruzi Infection

The first report on the effects of an AMP against T. cruzi was described in 1988. In that year, Jaynes et al. ^[73] demonstrated that two analogs of cecropin B were 50% and 100% effective in killing T. cruzi trypomastigotes in vitro. These analogs varied only slightly from cecropin B in their amino acid sequence homologies, and the charge distribution, amphipathic, and hydrophobic properties of the natural molecule were conserved. Since then, many natural and synthetic AMPs have shown activity against T. cruzi.

Bothrops atrox is a snake of great medical importance in the Amazon. Its venom is specialized for killing prey in nature, but it is also a source of peptides with antiprotozoal potential. For example, batroxicidin (BatxC) is a CPP extracted from its venom with trypanocidal activity ^[71]. Compared with Bz, BatxC was able to significantly reduce the number of free amastigotes (T. cruzi strain Y) in one assay after 24 h of incubation. The authors proposed that BatxC could kill epimastigotes by ROS generation, pore formation, and cell membrane degradation, inducing necrosis. Another antiprotozoal peptide is crotalicidin (Ctn), which is obtained from the venom gland of the rattlesnake Crotalus durissus terrificus. The peptide has a high selectivity index (>200) and is active against all morphological forms of the T. cruzi Y strain. The studies carried out reveal that the mechanism of cell death induced by Ctn seems to be necrosis and late apoptosis. Furthermore, the peptide showed a higher selectivity for the parasite compared with Bz ^[74]. M-PONTX-Dq3a is an AMP isolated from the venom of the ant species Dinoponera quadriceps. Two fragments derived from this AMP (M-PONTX-Dq3a[1-15] and [Lys]³-M-PONTX-Dq3a[1-15]) have been demonstrated to possess trypanocidal activities similar to those of the parent peptide against all three forms of the T. cruzi Y strain but with lower toxicity, better bioavailability, and a lower cost of production ^[85]^[86]. Due to their reduced peptide lengths, both fragments reached the clinical application phase. The mechanism of action appears to be the induction of parasitic necrosis through plasma membrane disruption and mitochondrial DNA fragmentation. Stigmurin (StigA25) is an AMP obtained from the venom gland of the scorpion Tityus stigmurus. StigA25 is stable to variations in pH and temperature and has antiparasitic activity of close to 100% against the T. cruzi Y strain, although its mechanism of action is still unknown ^[92]. [Arg]¹¹-VmCT1 is another antiprotozoal peptide isolated from the venom of the scorpion Vaejovis mexicanus with activity against the three developmental forms of T. cruzi through a necrotic mechanism of action ^[95]. Another marine CPP with anti-T. cruzi activity is tachyplesin-I. It is a host defense peptide from the horseshoe crab Tachypleus tridentatus with antileishmanial activity, as previously mentioned, and it even possesses anticancer properties ^[36]. Tachyplesin-I was more potent against trypomastigote forms of T. cruzi than epimastigote forms. Moreover, tachyplesin-I did not show any cytotoxic effect against Vero cells. Again, these differences might be explained by the distinct surface compositions of the parasite forms. According to Souto-Padrón ^[93], the epimastigote forms have the least negative surface charge of all the developmental stages of T. cruzi, whereas trypomastigotes have the most negative surface charge. In any case, the antiparasitic mechanism has not yet been described. A promising antichagasic hemocyanin fragment obtained from the Penaeus monodon shrimp is Hmc364-282 ^[84]. The peptide showed high selectivity against the epimastigote, trypomastigote, and amastigote forms of the T. cruzi Y strain, and was clearly more active and less cytotoxic than Bz. Necrosis appears to be the mechanism of action of the peptide. Polybia-CP is a wasp venom AMP that was reported to be a potent trypanocidal agent ^[90]. The peptide was able to inhibit the main developmental forms of T. cruzi with higher efficacy and less cytotoxicity than the standard Bz. The great efficacy of Polybia-CP against intracellular amastigotes confirmed its high penetrability into the parasite (the number of amastigotes decreased by 38% after 24 h of incubation). The mechanism of action by which Polybia-CP exerted its antichagasic activity was via an apoptosis-like process. The peptide did not damage the membrane of the parasite even at concentrations higher than its EC₅₀. These characteristics make Polibya-CP an interesting scaffold for the development of novel anti-Chagas therapies. The AMP melittin is the main toxic component in Apis mellifera venom. In vitro assays demonstrated that melittin affected all T. cruzi (CL Brener clone) developmental forms at low concentrations (up to 1 μg/mL) with low toxicity in mammalian cells ^[88]. It has been suggested that the mechanism of action of melittin depends on the parasite form. Accordingly, the main mechanism of cell death in epimastigotes and amastigotes would be autophagy. Conversely, in the trypomastigote form, melittin could produce cell death via apoptosis. In any case, melittin does not appear to affect the plasma membrane of the trypanosome. The in vitro activity and the different mechanisms of action confirm the great potential of melittin for the development of new therapies against neglected diseases such as Chagas disease. Dermaseptin 01 (DS 01) is a 29-residue-long peptide isolated from the skin secretions of the frog Phyllomedusa oreades. Bioassays revealed that DS 01 is a potent anti-T. cruzi Y strain agent. The peptide induced the death of the parasites by membrane disruption and cell leakage ^[80]. Pylloseptin 7 is a natural AMP isolated from the secretions of the frog Phyllomedusa nordestina with 1296-fold higher antitrypanosomal activity than Bz ^[91]. The peptide targets the plasma membrane of T. cruzi, leading to cell death by permeabilization. Pylloseptin 7 is a promising scaffold for the design of new antichagasic drugs. Defensin-α1 is a biologically active human AMP with demonstrated in vitro trypanocidal effects. Reported assays have indicated that this human peptide kills T. cruzi Tulahuen strain tripmastigotes and amastigotes in a peptide concentration-dependent and saturable manner ^[76]^[77]. It seems that its mechanism of action consists of the formation of pores in the membrane and the induction of nuclear and mitochondrial DNA fragmentation, leading to the destruction of the parasite. NK-2 is a shortened synthetic peptide formed by the cationic core-region-comprising residues 39 to 65 of porcine NK-lysine. Although both natural NK-lysine and NK-2 are capable of killing trypomastigotes (Tehuantepec strain), NK-2 demonstrated greater safety for human cells ^[89]. In addition, NK-2 also inhibited the replication of intracellular amastigotes. Although studies have been carried out, the mechanism of action of NK remains unclear, although the peptide quickly permeabilizes the parasite’s plasma membrane in minutes. This indicates that the parasite’s plasma membrane is targeted by NK-2, making the peptide a potential trypanocidal drug. Temporizin-1 is a synthetic hybrid peptide containing the N-terminal region of temporin A (produced by Rana temporaria), the pore-forming region of gramicidin, and a C-terminus consisting of alternating leucine and lysine ^[94]. Temporizin-1 is an improved version of temporicin created by shortening the four residues related to the gramicidin ionic channel pore, the origin of the unique mode of action of the peptide. The trypanocidal effect of temporicin-1 was studied in T. cruzi Y strain epimastigotes and was found to be dose-dependent, improving the antitrypanosomal activity of temporizine and gramicidin with less cytotoxicity. Regarding the mode of action, temporicin-1 seems to produce alterations in the mitochondria and nuclear DNA, albeit, curiously, causing no alterations to the plasma membrane. Its toxicity is based on the differences between the compositions of mammalian cell membranes and trypanosome membranes. Temporizin-1 appears to form ion channels in mammalian cell membranes, generating low toxicity. However, its toxicity towards trypanosomes seems to be attributed to an intracellular effect rather than pore formation.

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Subjects: Parasitology

Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :

Sara M. Robledo

Silvia Pérez-Silanes

Celia Fernández-Rubio

Ana Poveda

Lianet Monzote

Víctor M. González

Paloma Alonso-Collado

Javier Carrión

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Update Date: 21 Jul 2023

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